Symphytum: Hepatotoxicity of pyrrolizidine alkaloids

by Paul Bergner

Medical Herbalism 04-30-94 6(1): 10

The question of hepatotoxicity of pyrrolizidine alkaloids (PA) in herbal medicines has come to be a matter of clamorous debate in herbal circles. A number of national and international regulatory agencies have banned the sale of comfrey for internal use (WHO) after several cases of acute hepatotoxicity appeared after ingestion of comfrey products (Awang; Bergner 1993; Bergner 1989). A newborn infant also died in Switzerland after the mother had taken an herbal tea containing pyrrolizidine alkaloids during her pregnancy (Roulet et al.). Although the US Food and Drug Administration has not taken action here, the American Herbal Products Association has recommended against selling comfrey products for internal use. Some traditional herbalists have responded with disbelief that traditional plants were the cause of disease in these cases. In the interest of injecting some objective information into the debate, we provide here the biochemical mechanism of hepatotoxicity of PAs.

There is really nothing to debate about whether PAs as a class of compounds can cause the destruction of liver tissue in a condition known as hepatic veno-occlusive disease (HVOD). In HVOD, the cells lining the veins in the liver proliferate and choke off the veins. PAs in many plants are known to be cause HVOD. The first cases were observed in animals that were poisoned after foraging on PA-containing plants (Mattocks 1986). Epidemics have also been observed in human populations who consumed grain contaminated with PA-containing plants. Hepatic veno-occlusive disease has been reproduced experimentally in animals by giving them PA-containing plants (Mattocks). PAs themselves can vary widely in their toxicity; one alkaloid can be six or more times more toxic than another, and some are not toxic at all (Mattocks 1968). Furthermore, plants can vary widely in their PA content, from species to species, from one plant part to another, and from one season to another.

PAs themselves are usually of only low reactivity. The presumed basis for their toxicity is that a portion of ingested PAs are converted to toxic pyrroles by the liver enzymes, and immediately begin to destroy liver tissue. Thus the liver’s attempt to alter the compound to make it excretable in fact turns it into a highly reactive toxic substance. In rats, the process begins within five minutes of ingestion. Because the toxic pyrroles are formed in the liver, they tend to concentrate there, but have also been found in the lungs, heart, spleen, and kidney. Some of the pyrroles are excreted in the urine, but others are bound strongly to the tissue where they continue to damage adjacent tissue that they come in contact with. There is a direct correlation between the amount of PAs consumed and the amount of liver damage.

Thus PA poisoning is insidious: the toxic pyrrole substances are created by the liver’s natural attempt to eliminate the non-toxic PAs.

Clinical question:

Will milk thistle seed protect from PA poisoning?

Milk Thistle seed is a well-known hepatoprotectant. It is assumed to work through several mechanisms, including strengthening the cell walls of liver cells, promoting regeneration of liver cells, and protection through antioxidant effects. It is unlikely to be of much clinical use in poisoning by pyrrolizidine alkaloids, however, because PAs themselves are not toxic. It is only after they have entered the liver cells that they are transformed into toxic pyrroles, which destroy the cell from within. Furthermore, by an unknown mechanism, the pyrroles cause a proliferation of cells lining the veins of the liver, choking them off. Milk Thistle seed has no know protective effect on these liver veins. Finally, even if the pyrroles were prevented from damaging the liver, they would damage some other tissue. They are highly reactive, and could injure the lungs, heart, spleen, or kidney before they were excreted.


Awang D. “Comfrey update.” HerbalGram 1991;(25):20-23

Bergner P. Letter. Medical Herbalism 1993;5(4):3

Bergner P. “Comfrey, coltsfoot, and pyrrolizidine alkaloids,” Medical Herbalism 1989 1(1):1-5

Mattocks AR, Chemistry and Toxicology of Pyrrolizidine Alkaloids. Academic Press. London. 1986.

——. “Toxicity of pyrrolizidine alkaloids.” Nature 1968;217:723-729

Roulet M, Laurini R, Rivier L, Calame A. “Hepatic veno-occlusive disease in newborn infant of a woman drinking herbal tea.: J Pediatr 1988; 112(3):433-436

WHO International program on chemical safety. 1988. Environmental Health criteria 80: Pyrrolizidine alkaloids. World Health Organization. Geneva

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